Our objectives are several fold: A. To produce radiation resistant mutants from a stable strain of mammalian cells growing in various environments of radiation and in combination with various carcinogens and chemotherapeutic agents. Radiations of differing LET are also to be used. B. To quantitate the overall mutation rate for radiation resistance as a function of LET and dose rate including the simulation of a fractionated radiation therapy regimen. C. To elicit the basic mechanism of the induction of mutants by radiation and to investigate the possibility of synergism with other mutagenic agents. D. To identify, describe and assess biochemical, biophysical and cytological differences between the mutants and the parent strain. The attainment of these primary objectives will sharply extend our understanding of radiation resistance and perhaps lead to new radiation modifiers in cancer radiotherapy. Further, quantitative information on the production of radioresistant mutants as a function of dose delivery could lead to new fractionation schedules designed to minimize radioresistant tumor regrowth during and after therapy. Lastly, quantitation of mutation rates due to radiation in conjunction with other agents could have impact in both radiotherapy and regulation of environmental contaminants.